Herpesviruses are a family of large double stranded DNA-containing viruses many members of which are important human pathogens. A ubiquitous property of the herpesviruses is their capacity to cause both acute (productive) and latent infections in the human host, each of which is characterized by marked differences in patterns of viral transcription, DNA replication and in DNA structure.
Members of the herpesvirus family which are human pathogens include herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, Epstein Barr virus, cytomegalovirus, human herpes virus type 6, human herpes virus type 7, and that human herpesvirus which is associated with Kaposi's sarcoma (Chang et al., 1995, Science 266:1865-1869). Of these, herpes simplex virus type 1 (HSV-1) has been most intensively studied. This virus is the causative agent of a variety of diseases in humans including, but not limited to, gingivostomatitis, genital herpes, meningoencephalitis, keratoconjunctivitis, eczema herpeticum and systemic herpes virus disease of the newborn.
The herpes simplex virus type 1 (HSV-1) genome is a linear double-stranded DNA molecule composed of two unique components, designated unique long (UL) and unique short (US), each of which is flanked by inverted repeat sequences (Hayward, et al., 1975, Proc. Natl. Acad. Sci. USA. 72:4243-4247; McGeoch et al., 1988, J. Gen. Virol. 69:1531-1574). The HSV-1 genome contains three origins of DNA replication, one located within U.sub.L (oriL) and two within the repeat sequences flanking U.sub.S (oriS) (Challberg et al., 1989, Ann. Rev. Biochem. 58:671; Spaete et al., 1985, Proc. Natl. Acad. Sci. USA 82:694; Stow et al., Virology 130:427).
Expression of HSV-1 genes during productive infection proceeds in a coordinate and sequential manner (Honess et al., 1974, J. Virol. 14:8-19). The classification of HSV-1 proteins into broad sequential groups, immediate-early (IE), early (E), delayed early (DE), and late (L), is based on the kinetics of synthesis of individual viral transcripts and proteins, the effects of various metabolic inhibitors on DNA, RNA and protein synthesis, and studies using viral mutants.
In contrast to the complex sequence of events which occurs during productive infection, viral gene expression during latency is relatively simple. In latently infected cells, viral gene expression is limited to the latency-associated transcripts (LATs), a family of transcripts ranging in size from 2.0 to &gt;8 kilobase pairs (kb) (Stevens et al., 1987, Science 235:1056-1059; Spivak et al., J. Virol. 61:3841-3847; Zwaagstra et al., 1990, J. Virol. 64:5019-5028). The factors which mediate the switch from productive infection to latency and vice versa are not known.
It has been reported that treatment of HSV-1 latently infected mice with a combination of U.V. irradiation, cyclophosphamide and dexamethasone results in an increased level of reactivation of virus in the mouse eye compared with treatment with cyclophosphamide and dexamethasone alone. Once reactivation has begun, treatment with cyclophosphamide and dexamethasone may increase the duration of virus shedding from the eye (Shimeid et al., 1990, J. Gen. Virol. 71:397-404; Rootman et al., 1988, Investigative Opthalomology and Visual Science 29/3:351-356).
Glucocorticoid response elements (GREs) are DNA sequences that serve as binding sites for a hormone-inducible transcription-activating complex. According to the current model, steroid hormones bind to their specific receptors located within the cytoplasm (for glucocorticoids) and the nucleus (for progestins and estradiol). Formation of glucocorticoid/receptor complexes in the cytoplasm is followed by translocation of these complexes to the nucleus. Hormone/receptor complexes within the nucleus bind to a GRE and activate transcription of cellular genes. A GRE in its simplest form has been defined by the palindromic sequence 5'-AG.sup.A /.sub.G ACAnnnTGT.sup.T /.sub.C CT-3' (SEQ ID NO:1) (Kupfer et al., 1990, J. Virol., 64: 1984-1990; Berg, 1989, Cell 57: 1065-1068). A GRE was first identified as a element which responded to glucocorticoids, but is now recognized as the common response element for glucocorticoids, progestins, mineralocorticoids and androgens (Schreidereit et al., 1983, Nature 304:749-752; Beato, 1989, Cell 56:335-344). The distinct physiological effects of the different hormones result from differences in the levels of hormone receptor expression within a cell, enzymatic effects on different receptors prior to binding of complexes to DNA, and differential interaction with other sites on the DNA (Pearce, Steroids, 1994; 59: 153-159).
Immunosuppression of humans is frequently associated with reactivation of herpesvirus infection (including HSV) and recurrence of clinical disease. Until the instant invention, this reactivation was believed result from the inability of the immunosuppressed host to clear virus during spontaneous reactivation. The instant invention establishes a direct role for immunosuppressive compounds in virus replication and reactivation, and thereby provides an understanding of the mechanism by which virus is reactivated in the immunosuppressed host. Thus, the instant invention satisfies a long felt need for methods and compositions designed to facilitate immunosuppression of a host, which immunosuppression does not result in reactivation and replication of virus.